CD8 T cells play an important role in controlling viral infections as well as intracellular bacterial and parasitic infections. It is now clear that CD8 T cells are also involved in immunity against tumors and there is considerable interest in cancer immunotherapy that stimulates CD8 T cell responses. Thus, understanding the mechanisms that regulate antigen specific CD8 T cell responses is critical not only for the rational design of vaccines but also for development of novel approaches to enhance CD8 T cells for immunotherapy. Genome- wide transcriptional profiles of antigen specific CD8 T cells during acute infection have been extensively studied to elucidate the molecular basis of differentiation process from naive to effector to memory T cells. One of the interesting features obtained from such studies is downregulation of transcripts related to translation in effector CD8 T cells compared to naive CD8 T cells. Similarly, transcriptional inhibition of mRNAs associated with translation has been also observed in memory CD8 T cells repeatedly stimulated with multiple rounds of acute infection. Furthermore, transcriptional downregulation of a group of mRNAs important for translation has been reported in exhausted CD8 T cells that arose after chronic infection. These data strongly suggest that translation plays an essential role in regulation of antigen specific CD8 T cell responses during acute and chronic infections. However, translational control in antigen specific CD8 T cells in vivo has not been well studied, and thus understanding translational regulation is a new frontier of research for CD8 T cell immunity. We have recently tackled this important issue, and have shown that translation is actively regulated during the differentiation of CD8 effector T cells. Our long-term objective of this NIH grant application is to understand the role of translational regulation in the generation of effector, memory, and exhausted CD8 T cells, and to use this information to develop novel approaches of vaccination and control of chronic infections including viral- mediated cancers. Our proposed studies in this application represent a new direction of research in the area of T cell memory and exhaustion, and will provide crucial information toward our long-term objective. The following specific aims are proposed: Specific Aim 1: To examine the role of eIF4E-dependent translation in the fate decisions involved in the formation of terminal effector and memory precursor CD8 T cells during acute infection. Specific Aim 2: To understand how translational regulation dependent on mTORC1-S6K-eIF4A signals regulates the fate of effector CD8 T cell differentiation during acute infection. Specific Aim 3: To understand translational regulation of CD8 T cell exhaustion during chronic infection.